Means for constraining a rumen drug delivery device in a rolled configuration

ABSTRACT

Improved means for constraining a rumen drug delivery device in a rolled configuration, said means comprising a laminate, which may be perforated, comprising a water-permeable material having a low friction surface in the presence of water, said material being bonded by means of a water-dispersible pressure sensitive adhesive to a repulpable tape, said tape having said water-dispersible pressure sensitive adhesive on both its surfaces; a laminate comprising a flexible, water-permeable polymeric material bonded between the low friction surface material and the repulpable tape; and devices constrained by said means.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to improved means for constraining a rumen drugdelivery devices in a rolled configuration. More particularly, itrelates to laminates comprising a water permeable material having a lowfriction surface in the presence of water, said material being bonded toa repulpable tape having a water-dispersible adhesive on both surfaces;to laminates comprising a flexible, water-permeable polymeric materialbonded between the low friction surface material and the repulpabletape; and to devices so constrained.

2. Description of Related Art

Rumen drug delivery devices constrained in a rolled-up configuration byappropriate constraining means are disclosed in U.S. Pat. Nos. 4,228,149and 4,601,893, the disclosures of which are incorporated herein byreference. U.S. Pat. No. 4,228,149 discloses sheets of drug-containingethylene vinyl acetate copolymer, which may be coated on both surfacesby a water soluble polymer film, constrained in a rolled-upconfiguration. U.S. Pat. No. 4,601,893 teaches laminate devicescomprising a drug-containing ethylene vinyl acetate copolymer sheetsandwiched between two coextensive films of ethylene vinyl acetatecopolymer and having one or more macro-perforations extending throughall laminae, said laminae being constrained in a rolled-upconfiguration. U.S. application Ser. No. 170,495, filed Mar. 21, 1988,describes improved delivery devices of the type disclosed in U.S. Pat.No. 4,601,893. The improved devices are identical to those of U.S. Pat.No. 4,601,893 in construction but, in order to enhance their unrollingin the use environment, have been subjected to an annealing processprior to being constrained in a rolled configuration. The annealingprocess is conducted at a temperature of from about 40° C. to about 80°C., a range of about 43° to 60° C. being preferred. The time ofannealing varies with the temperature of annealing. Further, the timeand temperature vary with the manner in which the devices being annealedare arranged for the annealing step. The U.S. Pat. No. 4,601,893 typedevices can be punched or cut to their approximate or actual size priorto annealing or the sheets from which the individual devices are punchedcan be annealed prior to punching out individual devices. The individualdevices or sheets can be annealed individually or they can be stackedone upon the other to a height determined only by the size of theannealing equipment. The sheets can also be rolled for ease of handlingprior to annealing and punching. In any case, stacking of the devices orsheets or rolling of the sheets generally requires temperatures towardthe lower end of the indicated range and times toward the upper end ofthe range. Each arrangement requires determination of the conditions foroptimum annealing. Temperatures which are too high may cause sticking ofstacked devices, sheets or rolled sheets. Lower temperatures and longertimes are best suited for stacked or rolled materials. For example, aroll of sheet material comprising a core 0.075 inches (1.91 mm) thickand outer layers each 0.05 inch (1.27 mm) thick, rolled on a 14 inch(35.56 cm) spindle to an overall diameter of 94 inches (238.76 cm), isdesirably annealed for up to 96 hours at 43° C. Thus, considering theparameters of temperature and overall thickness of the material to beannealed from about 96 to 4 hours is practical.

A further modification of the delivery devices of U.S. Pat. No.4,601,893 is described in U.S. application Ser. No. 170,529, filed Mar.21, 1988. Said modification comprises U.S. Pat. No. 4,601,893 typedevices which have been coated on one side with an elastomer prior tobeing constrained in a rolled configuration. The elastomer coated sidebecomes the outer side of the device when the device is placed in arolled configuration. The elastomer coated side improves the elasticityof the devices such that they recover or unroll from their constrainedconfiguration to a greater extent and at a faster rate. The term"elastomer" as used herein is intended to embrace materials that, whenstretched, snap back to their original or near-original shape. Morespecifically, it embraces thermoset and thermoplastic elastomers orelastoplastics, representative of which are styrene-diene blockcopolymers, polyurethanes, nitrile rubbers, olefinics and copolyesterethers, and preferably silicon rubbers (e.g. polydimethylsiloxanes). Ineach of said patents and applications the constraining means comprises abiodegradable material such as gelatin string or tape, water solubleadhesive or paper.

Within the use environment; i.e., the rumen, the constraining means isdissolved, destroyed, ruptured or otherwise removed to allow therolled-up device to revert to its original, or near-original sheetconfiguration to prevent its expulsion from the rumen.

It has been observed that the prior art devices described above aresometimes expelled by the ruminant because of untimely removal of theconstraining means within the rumen. Additionally, difficulty is oftenencountered upon oral administration of the constrained devices to youngruminants. Premature removal of the constraining means and subsequentunrolling of the constrained device or slow transit of the constraineddevice can lead to dosing problems. Thus, the need for improvedconstraining means for rumen drug delivery devices which will facilitatedosing of ruminants therewith and enable timely change of configurationin the rumen and eliminate expulsion of the device by the ruminant.

SUMMARY OF THE INVENTION

There has now been found improved constraining means which overcome theabove-cited difficulties. The herein-described constraining meansprovide a low friction surface to facilitate dosing of the device,afford timely change in geometry of the rolled-up device within therumen, avoid premature unrolling of the devices on dosing, are stableand non-toxic.

DETAILED DESCRIPTION OF THE INVENTION

The improved constraining means of this invention comprises awater-permeable material having a low friction surface in the presenceof water, said material being bonded by means of a water-dispersiblepressure sensitive adhesive to a repulpable tape which is coated on bothsurfaces with said adhesive. A modification of the above-describedlaminate comprises one having a flexible, water-permeable polymericmaterial bonded between the low friction surface material and therepulpable tape. A still further modification comprises a laminatecomprising a flexible, water-permeable polymeric material sandwichedbetween two sheets of a water-permeable material having a low frictionsurface in the presence of water, one surface of which is bonded bymeans of a water-dispersible pressure sensitive adhesive to a repulpabletape which is coated on both surfaces (doubly coated) with saidadhesive. Also included in this invention are rolled-up rumen drugdelivery devices constrained by the herein-described improvedconstraining means.

Water-dispersible pressure sensitive tapes and repulpable tapes coatedwith said water-dispersible pressure sensitive adhesives are describedin U.S. Pat. Nos. 3,865,770; 3,441,430; 4,413,080; and 4,569,960. Suchtapes find extensive use in the paper-making industry. The disclosuresof each of said patents is incorporated herein by reference.

The favored water-permeable material having a low friction surface inthe presence of water is nitrocellulose. As the outermost, or top layer,of the laminates described herein, the nitrocellulose facilitates oraladministration of the constrained devices in view of the low-frictionsurface which it acquires in the presence of the saliva in theruminant's esophageal passage.

In one form of the herein described constraining means, thenitrocellulose film is bonded directly to one surface of the doublyadhesive coated repulpable tape. The other adhesive coated surface, ofthe tape is, of course, bonded to the rolled-up drug delivery device soas to constrain it in said configuration. This form of constrainingmeans may, if increased flow of environmental fluid to the waterdispersible adhesive is desired, be perforated, especially withmacroholes ranging from about 0.5-5 mm in diameter, prior to its beingapplied to the rolled-up device. The holes are normally circular butcould be any shape such as, for example, ovals, triangles, squares,hexagons, etc. The perforations tend to accelerate removal of theconstraining means.

In a modified, and favored, form of the improved constraining means ofthis invention, a flexible, water-permeable polymeric material,preferably cellophane, is bonded between the low friction surfacematerial and the repulpable tape. The cellophane serves to enhanceremoval of the constraining means and unrolling of the rolled-up device.In addition to cellophane other water-permeable polymers, such aspolyvinyl acetate, polymethylmethacrylate, polyethylmethacrylate,polyvinylchloride, cellulose acetate and polydimethylsiloxane, can beused.

A preferred modification of the improved constraining means of thisinvention comprises a laminate comprising a flexible, water-permeablepolymeric material, such as is described above, sandwiched between twosheets of a water-permeable material (e.g. nitrocellulose) having a lowfriction surface in the presence of water, one surface of which isbonded to a repulpable tape doubly coated with a water-dispersiblepressure sensitive adhesive. The thickness of said coated cellophane canrange from about 0.3 to 3.0 mils (0.0076 to 0.076 mm.). Cellophanecoated on both surfaces with nitrocellulose, i.e., sandwiched betweennitrocellulose, is commercially available from BCL America, Inc. ofMalvern, PA. 19355, product grade 345 PS-41. It has a thickness of about0.9 mil (0.023 mm.).

Each of the forms of the constraining means described herein mayoptionally have macroperforations made in them, especially at thatportion thereof where the said means abut or overlap when placed aboutthe rolled-up delivery device to enhance unrolling of the device in theuse environment.

The laminates of this invention are conveniently constructed bycontacting the individual layers of the lamina, e.g., nitrocellulose, orcellophane coated on both sides with nitrocellulose, with the repulpabletape doubly coated with a water-dispersible pressure sensitive adhesive.Suitable water-dispersible pressure sensitive adhesives are well knownin the art.

Representative water-dispersible pressure sensitive adhesives are thosecomprising a copolymer of monomeric acrylic acid esters and vinylcarboxylic acid monomer, said copolymer being partially neutralized witha secondary or tertiary alkanolamine, or an alkali metal hydroxide. Oilyplasticizing compounds such as water-soluble polyoxyethylenes; andtackifiers such as reaction products of acid rosins and alkanolaminesare added thereto. Such adhesives and their use to make repulpable tapesare described in U.S. Pat. Nos. 3,865,770; 4,413,080, 4,569,960 andreferences cited therein, incorporated herein by reference.

Illustrative of such adhesives described in said patents are thosecomprising:

(I)

(a) a copolymer of monomers consisting essentially of

(1) about 90-20 parts by weight monomeric acrylic acid ester ofnon-tertiary alkyl alcohol the molecules of which have 1 to 4 carbonatoms; and

(2) about 10-80 parts by weight vinyl carboxylic acid monomercopolymerizable with said acrylic acid ester, at least a number of thecarboxyl groups in said acid monomers sufficient to constitute about3-22% the weight of said copolymer, having been neutralized by reactionwith a secondary or tertiary alkanolamine containing at least 4 carbonatoms; and

(b) 0-400 parts by weight of at least one water-dispersibletack-promoting material selected from the class consisting of the oilyplasticizing water-soluble polyoxyethylene compounds and the tackifyingreaction products of acid rosins and alkanolamines; or

(II) the blended reaction product of

(a) 100 parts by weight of a copolymer of monomers consistingessentially of

(1) about 75-85 weight percent of at least one monomeric acrylic acidester of nontertiary alkyl alcohol, and correspondingly,

(2) about 25-15 weight percent of vinyl carboxylic acid,

(b) about 35-100 parts by weight of acidic rosin or rosin derivative,

(c) sufficient potassium hydroxide to neutralize about 30-45% of thecombined carboxyl groups of the copolymer and rosin or rosin derivative,

(d) sufficient sodium hydroxide, lithium hydroxide, or a combination ofsodium and lithium hydroxide to neutralize about 20-45% of said carboxylgroups, and

(e) about 100-225 parts by weight of oily plasticizing water-solublepolyoxyethylene compound; or

(III) the blended reaction product of

(a) 100 parts by weight of a copolymer of monomers consistingessentially of

(1) about 60-85 weight percent of at least one monomeric acrylic acidester of nontertiary alkyl alcohol having 4-14 carbon atoms, andcorrespondingly,

(2) about 40-15 weight percent of vinyl carboxylic acid,

(b) about 50 to 250 parts by weight of ethoxylated plasticizingcomponents, sufficient to impart adhesion values such as to cause theadhesive to delaminate kraft paper when tested as described herein,consisting essentially of at least one of the following:

(1) up to about 125 parts by weight, but not so much as to causeadhesive separation, of one or more OH-functional ethoxylatedplasticizers and

(2) one or more electrolyte-tolerant complex and acidic esters ofphosphoric acid and an ethoxylated nonionic surfactant, and

(c) alkaline hydroxide consisting essentially of

(1) sodium hydroxide, lithium hydroxide, or both sodium hydroxide andlithium hydroxide, in an amount sufficient to enhance shear strength andminimize bleeding but insufficient to cause separation of anyOH-functional ethoxylated plasticizer present, not exceeding about 0.07hydroxyl equivalent if OH-functional ethoxylated plasticizer is the onlyplasticizing component present, and

(2) potassium hydroxide in an amount sufficient to promote watersolubility.

The constraining means of this invention should not substantiallyincrease the overall diameter of the constrained device at the point ofconstrainment to a thickness that would give rise to dosing problemswhen the constrained device is administered to a rumen. Thisrelationship between the thickness (diameter) of the rolled-up deviceand that of the constraining means will be recognized by those skilledin the art. Said individuals will appreciate the need to maintain thethickness of the constraining means to a minimum thickness consistentwith acceptable times of removal of the constraining means in the useenvironment. In general, constraining means of this invention having athickness of from about 1.3 to 10.0 mils (0.0013 to 0.010 inch; or 0.033to 0.254 ml.) afford acceptable release times. Such constraining meansare especially valuable when used to constrain delivery devices of U.S.Pat. Nos. 4,601,893 and 4,228,149. A typical device of U.S. Pat. No.4,601,893 for use in cattle, has, when rolled-up, a diameter of about2.54 cm.

The point of greatest tension in the constraining means occurs at thatsegment of the roll where the constraining means bridges the gap formedby its contact with the terminal edge of the outer layer of therolled-up device and the surface of the layer upon said outer layerends. The effect of this tension can be minimized by doubling thethickness of the overall length of the constraining means used.Alternatively, the effect can be minimized by placing a reinforcingstrip of said constraining means having the thickness disclosed aboveover said segment.

As will be appreciated the constraining means used can be of sufficientlength as to completely wrap about the rolled-up device, the endsthereof forming a butt joint. Alternatively, the constraining means canbe of such a length that the ends thereof overlap to a lesser or greaterextent when said means is placed about a rolled-up device. The extent ofoverlap should, for economic reasons, be less than that which wouldresult in a double thickness of constraining means. Still further, theconstraining means need not entirely wrap about the rolled-up device. Itshould, at the least, be in contact with the terminal end of the outerlayer of the rolled-up device and the surface of the layer upon whichsaid outer layer ends. The favored length of constraining means is thatrequired to completely wrap about the rolled-up device.

The improved constraining means of this invention are readily preparedby laminating the adhesive coated repulpable tape to the water-permeablepolymeric material having a low friction surface in the presence ofwater, e.g., nitrocellulose; or to the nitrocellulose coated cellophane,by known methods, care being taken to avoid formation of bubbles orwrinkles. The laminated tape is then cut to desired size. Perforationsmay be conveniently made either before or after cutting of the laminatedtape.

The removability of the constraining means of this invention in the useenvironment, e.g., the rumen of a ruminant, is determined by in vitro orin vivo methods. The in vitro method comprises placing the constraineddevice in water, or more appropriately a synthetic rumen fluid, at 40°C. on an incubator shaker (ca.80 excursions per minute) and observingthe time required for unrolling of the constrained device. The in vivomethod comprises administering the constrained device to a fistulatedruminant and observing the time required for unrolling of theconstrained device.

To further minimize dosing problems, the constrained devices desirablyhave plugs, e.g., polyethylene plugs, inserted into their open ends toconvert the hollow tube to substantially a rod like device.

EXAMPLE 1

A morantel tartrate containing device prepared according to Example 1 ofU.S. Pat. No. 4,601,893 was constrained in a rolled-up configurationwith a constraining means of this invention comprising a 8.9×7.6 cm widelaminate of 3M tape no. 900 and cellophane coated on both surfaces withnitrocellulose (product grade 345 PS-41). The ends of the tape whenwrapped around the device overlapped 0.635 cm.

When placed in water at 40° C. as described above, the constrainingmeans was removed in 40 minutes.

A similar device which had been stored at ambient temperature for 6months required 57 minutes for removal of the constraining means whenplaced in 40° C. water.

EXAMPLE 2

The constraining means of a constrained device prepared according toExample 1, when administered to a fistulated ruminant, was observed tobe removed within 40 minutes, resulting in unrolling of the device.

EXAMPLE 3

The experiment of Example 1 was repeated but using a tape in which 50perforations, each 2 mm in diameter, were made in the overlapping ends.

The constraining means was removed in 15 minutes when the constraineddevice was placed in 40° C. water.

EXAMPLE 4

A device prepared according to Example 2 of U.S. Pat. No. 4,228,149 isconstrained in a rolled configuration by a 8.9×7.6 cm wide laminate of3M tape no. 405 and cellophane coated on both surfaces withnitrocellulose. The laminate was sufficiently long so that the endsoverlapped 0.635 cm.

EXAMPLE 5

The procedure of Example 3 is repeated but using doubly coatedrepulpable tapes prepared using the adhesives of Example 29 of U.S. Pat.No. 4,569,960 and of Example 7 of U.S. Pat. No. 4,413,080.

EXAMPLE 6

Ten devices are prepared according to the procedure of Example 1 exceptthat, prior to being constrained, the devices are annealed at 50° C. for24 hours. The devices are then tested at varying time levels for theirability to unroll. All devices, even those stored at ambient temperaturefor 6 months, unrolled; i.e., the constraining means is removed, fromtheir original 2.5 cm cross-section diameter to a cross-section diameterwithin one hour sufficient to prevent their regurgitation by a ruminant.

EXAMPLE 7

Devices prepared according to Example 1 were administered to 100 youngruminants (approximately 100 kg in weight). No difficulty wasexperienced in dosing the animals and no devices were regurgitated byany of the animals.

EXAMPLE 8

Twenty devices prepared substantially according to Example 1 weredivided into two equal groups. Group A devices were placed in 40° C.water as described above and group B devices were administered tofistulated cattle, one device per animal. The times required for removalof the constraining means were recorded

    ______________________________________                                                 Average      Range of    Standard                                    Group*   Removal Time Removal Time                                                                              Deviation                                   ______________________________________                                        A -  in vitro                                                                              31 minutes   20-46 minutes                                                                           8 minutes                                 B -  in vivo 51 minutes   30-63 minutes                                                                           9 minutes                                 ______________________________________                                    

EXAMPLE 9

Nitrocellulose coated cellophane (BCL 345 PS 41) was coated with(Fitchburg Coated Products Inc., Scranton, PA 18501) WASH-AWAY™ adhesive(a blend of polyvinyl methyl ether, maleic anhydride and a phosphateester) to prepare a pressure sensitive constraining means with watersoluble adhesive. A device from Example 1 of U.S. Pat. No. 4,601,893 wasconstrained by the above-mentioned constraining means. The constraineddevice when immersed in water at 40° C. underwent removal of theconstraining means in 23 minutes.

We claim:
 1. A laminate to act as a constraining device, comprising awater-permeable material having a low friction surface in the presenceof water, said material being bonded by means of a water dispersiblepressure sensitive adhesive to a first surface of a repulpable tapehaving first and second surfaces, said tape having a second layer ofsaid water dispersible pressure sensitive adhesive on its secondsurface.
 2. A laminate according to claim 1 wherein the low frictionsurface material is nitrocellulose.
 3. The laminate according to claim 2wherein the water-dispersible pressure sensitive adhesivecomprises:(I)(a) a copolymer of monomers consisting essentially of(1)about 90-20 parts by weight monomeric acrylic acid ester of non-tertiaryalkyl alcohol the molecules of which have 1 to 4 carbon atoms; and (2)about 10-80 parts by weight vinyl carboxylic acid monomercopolymerizable with said acrylic acid ester, at least a number of thecarboxyl groups in said acid monomers sufficient to constitute about3-22% the weight of said copolymer, having been neutralized by reactionwith a secondary or tertiary alkanolamine containing at least 4 carbonatoms; and (b) 0-400 parts by weight of at least one water-dispersibletack-promoting material selected from the group consisting of the oilyplasticizing water-soluble polyoxyethylene compounds and the tackifyingreaction products of acid rosins and alkanolamines; or (II) the blendedreaction product of(a) 100 parts by weight of a copolymer of monomersconsisting essentially of(1) about 75-85 weight percent of at least onemonomeric acrylic acid ester of nontertiary alkyl alcohol, andcorrespondingly, (2) about 25-15 weight percent of vinyl carboxylicacid, (b) about 35-100 parts by weight of acidic rosin or rosinderivative, (c) sufficient potassium hydroxide to neutralize about30-45% of the combined carboxyl groups of the copolymer and rosin orrosin derivative, (d) sufficient sodium hydroxide, lithium hydroxide, ora combination of sodium and lithium hydroxide to neutralize about 20-45%of said carboxyl groups, and (e) about 100-225 parts by weight of oilyplasticizing water-soluble polyoxyethylene compound; or (III) theblended reaction product of(a) 100 parts by weight of a copolymer ofmonomers consisting essentially of(1) about 60-85 weight percent of atleast one monomeric acrylic acid ester of nontertiary alkyl alcoholhaving 4-14 carbon atoms, and correspondingly, (2) about 40-15 weightpercent of vinyl carboxylic acid, (b) about 50 to 250 parts by weight ofethoxylated plasticizing components, sufficient to impart adhesionvalues such as to cause the adhesive to delaminate kraft paper,consisting essentially of at least one of the following:(1) up to about125 parts by weight, but not so much as to cause adhesive separation, ofone or more OH-functional ethoxylated plasticizers and (2) one or moreelectrolyte-tolerant complex and acidic esters of phosphoric acid and anethoxylated nonionic surfactant, and (c) alkaline hydroxide consistingessentially of(1) sodium hydroxide, lithium hydroxide, or both sodiumhydroxide and lithium hydroxide, in an amount sufficient to enhanceshear strength and minimize bleeding but insufficient to causeseparation of any OH-functional ethoxylated plasticizer present, notexceeding about 0.07 hydroxyl equivalent if OH-functional ethoxylatedplasticizer is the only plasticizing component present, and (2)potassium hydroxide in an amount sufficient to promote water solubility.4. The laminate according to claim 3 wherein the pressure sensitiveadhesive is that of claim 3, part I.
 5. A laminate according to claim 4,said laminate having a flexible, water-permeable polymeric materialbonded between the low friction surface material and the repulpabletape.
 6. The laminate according to claim 5 wherein the low frictionsurface material is nitrocellulose and the flexible water-permeablepolymeric material is a flexible cellophane.